Dissecting the virulence and antibiotic resistance potential of Klebsiella pneumonaie in disparate environments

剖析不同环境中肺炎克雷伯菌的毒力和抗生素耐药性潜力

• 批准号: RGPIN-2021-03944
• 负责人: Lee, Amy
• 金额: $ 2.19万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761198
• 关键词: Dissecting; virulence; antibiotic; resistance; potential

Klebsiella pneumoniae is ubiquitously distributed in the environment, including in water, soil, plants, insects, aquatic and agricultural animals, and humans. Due to its diverse ecological distribution and its ability to acquire antimicrobial resistance (AMR) genes through horizontal gene transfer, multi-drug resistant (MDR) K. pneumoniae is considered to be a major AMR trafficker. In contrast, hypervirulent K. pneumoniae has limited AMR genes but causes invasive infection. Even though AMR genes and virulence factors are both encoded by mobile genetic elements such as plasmids, we rarely observe convergence of these two phenotypes in one strain. One potential explanation based on genomic comparison of diverse K. pneumoniae is that the MDR and the hypervirulent lineages may prefer different ecological niches. However, there has not been a systematic comparison between MDR and hypervirulent strains to define their growth in different environments. Moreover, the transcriptional regulation and the gene sets required by K. pneumoniae to survive in disparate environments are not clear. The overarching goal of the proposed research program is to experimentally address whether there are growth (fitness) differences between K. pneumoniae lineages in disparate conditions, ultimately to provide functional insights into its ecological niches and its ability to maintain or transfer AMR genes. Our hypothesis is that the transcriptional and genetic networks in MDR lineages allow these strains to tolerate a wider range of growth conditions and to maintain AMR compared to hypervirulent lineages. We will test this hypothesis using comparative genomics, transcriptomics, fitness assays and phenotyping of different K. pneumoniae clonal types sampled from diverse environments. We will tackle three short-term questions over the next five years: (1) How do different K. pneumoniae strains grow and maintain AMR genes across diverse environments? (2) What is the transcriptional regulation that allows K. pneumoniae to survive in these disparate conditions? and (3) What are the sets of genes essential for K. pneumoniae to survive and maintain AMR genes in those environments? The proposed research will provide insights into the metabolic potential of K. pneumoniae and enhance our understanding of its role in maintaining and distributing AMR genes from environmental sources. This innovative work will provide the first comprehensive functional characterization of both K. pneumoniae MDR and hypervirulent strains, ultimately developing better intervention strategies to prevent K. pneumoniae as an AMR trafficker. Importantly, our study will provide insights into potential mechanisms by which K. pneumoniae with both hypervirulence and multi-drug resistance may arise. These results will allow us to thwart the emergence of hypervirulent K. pneumoniae superbug and will be of interest to clinical and One Health researchers working on AMR.

肺炎克雷伯氏菌广泛分布于环境中，包括水、土壤、植物、昆虫、水生和农业动物以及人类。由于其生态分布的多样性和通过水平基因转移获得抗菌素耐药（AMR）基因的能力，多药耐药（MDR）K。pneumoniae被认为是主要的AMR贩运者。与此相反，高毒力K.肺炎克雷伯氏菌具有有限的AMR基因，但引起侵袭性感染。尽管AMR基因和毒力因子都是由质粒等移动的遗传元件编码的，但我们很少观察到这两种表型在一个菌株中的收敛。一个可能的解释是基于不同K.耐多药和高毒力的谱系可能更喜欢不同的生态位。然而，还没有一个系统的比较MDR和高毒力菌株，以确定它们在不同的环境中的生长。此外，还对K. pneumoniae在不同环境中的生存能力尚不清楚。 建议的研究计划的首要目标是实验解决是否有生长（健身）K之间的差异。pneumoniae谱系在不同的条件下，最终提供其生态位的功能性见解及其维持或转移AMR基因的能力。我们的假设是，MDR谱系中的转录和遗传网络允许这些菌株耐受更广泛的生长条件，并与高毒力谱系相比维持AMR。我们将使用比较基因组学、转录组学、适应性测定和不同K. pneumoniae克隆类型从不同的环境中取样。我们将在未来五年内解决三个短期问题：（1）如何不同的K。pneumoniae菌株在不同的环境中生长并保持AMR基因？(2)是什么样的转录调控使K。在这些完全不同的环境中生存吗K.在这些环境中生存和维持AMR基因的能力？这项研究将为钾的代谢潜力提供新的见解。pneumoniae，增强我们对它在维持和分布环境来源的AMR基因中的作用的理解。这项创新性的工作将提供第一个全面的功能表征的K。pneumoniae MDR和高毒力菌株，最终开发出更好的干预策略，以防止K。肺炎是AMR的贩运者。重要的是，我们的研究将为K。同时具有超强毒力和多药耐药性的肺炎。这些结果将使我们能够阻止高毒力K.这是一种新的肺炎超级细菌，将引起临床和One Health研究人员对AMR的兴趣。